Retinoids, including vitamin A (retinol) and its metabolites such as all-trans retinoic acid (RA), regulate cell proliferation and differentiation (Gudas et al., 1994, The Retinoids: Biology, Chemistry, and Medicine, eds Sporn M B, Roberts A B, & Goodman D S (Raven Press, New York), pp 443-520). RA regulates gene expression by binding and activating retinoic acid receptors (RARs α, β, and γ) and retinoid X receptors (RXRs α, β, and γ), transcription factors that heterodimerize and associate with retinoic acid response elements (RAREs) (Chambon P, 1996, FASEB J. 10:940-954; Mongan N P & Gudas L J, 2007, Differentiation 75(9):853-870; Tang X H & Gudas L J, 2011, Annu Rev Pathol 6:345-364.)
Retinoid X receptors (RXRs) play a key role within the nuclear receptor (NR) superfamily and can form heterodimers with many other nuclear receptors, including RARs, PPARs, liver X receptors (LXR), farnesoid X receptor (FXR) (Perez E, Bourguet W, Gronemeyer H, & de Lera A R, 2012, Biochim Biophys Acta 1821(1):57-69.), and vitamin D receptor (VDR) (Perez E, Bourguet W, Gronemeyer H, & de Lera A R, 2012, Biochim Biophys Acta 1821(1):57-69; Germain P, et al. 2006, Pharmacol Rev 58(4):760-772.). Because RXRs participate in many nuclear receptor signaling pathways, they have been a target for drug discovery (Perez E, Bourguet W, Gronemeyer H, & de Lera A R, 2012, Biochim Biophys Acta 1821(1):57-69.).
The retinoic acid receptor (RAR) is a type of nuclear receptor that is activated by both all-trans retinoic acid and 9-cis retinoic acid. The effects of RA on cells and tissues are known to occur through the activation of retinoic acid receptors (RARα, RARβ, and RARγ) and their isoforms (Chambon P, 1996, FASEB J. 10:940-954; Tang X H & Gudas L J, 2011, Annu Rev Pathol 6:345-364).
Head and neck cancer is a group of cancers that start in the lip, oral cavity (mouth), nasal cavity (inside the nose), paranasal sinuses, pharynx, and larynx. These cancers are biologically similar, with 90% of head and neck cancers are squamous cell carcinomas originating from the mucosal lining (epithelium) of these regions. These cancers are frequently aggressive in their biologic behavior, and patients with these types of cancer are at a higher risk of developing another cancer in the head and neck area.
Natural and synthetic retinoids have shown efficacy in the prevention and treatment of human cancers including leukemia, breast and lung cancers (Connolly R M, Nguyen N K, & Sukumar S, 2013, Clin Cancer Res 19(7):1651-1659; Dragnev K H, et al., 2007, Clin Cancer Res 13(6):1794-1800; Dragnev K H, et al., 2011, Cancer Prev Res (Phila) 4(6):818-828; Gniadecki R, et al., 2007, Br J Dermatol 157(3):433-440.). Bexarotene inhibits cell proliferation and induces cellular senescence and apoptosis in a mouse breast cancer model (Shilkaitis A, Bratescu L, Green A, Yamada T, & Christov K, 2013, Cancer Prev Res (Phila) 6(4):299-308.), and modulates expression of genes related to the cell cycle, cell differentiation/apoptosis, and cell adhesion/migration in a mouse breast cancer model (Abba M C, et al., 2009, Cancer Prev Res (Phila) 2(2):175-184.) and in human normal mammary epithelial cells (Kim H T, et al., 2006, Cancer Res 66(24):12009-12018.). RARγ also mediates RA-induced growth arrest and apoptosis of neoplastic mouse papilloma cell lines (Hatoum A, El-Sabban M E, Khoury J, Yuspa S H, & Darwiche N, 2001, Carcinogenesis 22(12):1955-1963.).
Head and neck cancer is often treated with some form of surgery, with the goal of removing the cancerous cells entirely. This can be particularly difficult if the cancer is near the larynx and can result in the patient being unable to speak. Surgery is also commonly used to remove some or all of the cervical lymph nodes to prevent further spread of the disease. Radiation therapy may also play an important role. Treatment with 13-cis RA, which can be isomerized to RA, a pan-RAR agonist, resulted in reductions in the sizes of oral leukoplakias in patients (Connolly R M, Nguyen N K, & Sukumar S, 2013, Clin Cancer Res 19(7):1651-1659; Lippman S M, et al., 1993, N Engl J Med 328(1):15-20.). The effectiveness of radiation and chemotherapy, however, is often limited; while side effects may be significant.
Head and neck cancer is strongly associated with certain environmental and lifestyle risk factors, including tobacco smoking, alcohol consumption, UV light, particular chemicals used in certain workplaces, and certain strains of viruses, such as human papillomavirus (HPV) and Epstein-Barr virus (EBV). Cigar smoking is an important risk factor for oral cancers as well. Head and neck cancers, however, are often not diagnosed early enough for the most effective treatment. For example, about 60-70% of oral cavity carcinoma cases are diagnosed only after the tumors have become locally advanced (Lippman S M, Sudbo J, & Hong W K, 2005, J Clin Oncol 23(2):346-356.). Therefore, there is a need for alternative treatments that prevent or slow the progression of head and neck cancer using novel pharmaceutical compositions.